The goals of this project relate to the use of newly discovered naturally occuring tumor inhibitors as chemical templates for the design of new cancer chemotherapeutic agents. The proposed work will study the significance of certain pharmacophoric groups contained within these molecules: specifically, factors such as ring strain, steric hindrance, and stereochemical inter-relationships between pharmacophoric groups will be studied. Within the context of stated goals relative chemical reactivities of specific functional groups will be studied, factors which influence the reactivity will be examined and related to anti- tumor activity and toxicity. The proposed program involves th synthesis of trichothecane anti tumor mycotoxins as well as certain trichothecane analogs. The synthesis of aromatic A-ring trichothecane analogs has been proposed. The route proposed is generally applicable to a wide variety of aromatic analogs and may also be of value in the synthesis of aliphatic naturally occurring trichothecanes. The proposed route involves the initial condensation of a 3-chlorocyclopentenyl compound with an appropriate phenol; thermal rearrangement of the resulting ether generates the trichothecane carbon backbone which, through a series of reactions, may be converted to the tricyclic trichothecane skeleton. A similar route is being studied in the aliphatic series. In addition to the route outlined above, alternate schemes are being examined. These alternate schemes involve possible new types of olefinic cyclization reactions and cyclizations involving chloroepoxides.